NM_000719.7:c.5408G>A

Variant names:

• chr12-2679760-G-A
• rs201918158
• NM_000719.7:c.5408G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_000719.7(CACNA1C):​c.5408G>A​(p.Arg1803Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000195 in 1,587,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.61

Genes affected

CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]

CACNA1C-AS1 (HGNC:):

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1943275).
• BP6: Variant 12-2679760-G-A is Benign according to our data. Variant chr12-2679760-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219520.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5408G>A	p.Arg1803Gln	missense_variant	Exon 42 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5408G>A	p.Arg1803Gln	missense_variant	Exon 42 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5408G>A	p.Arg1803Gln	missense_variant	Exon 42 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5408G>A	p.Arg1803Gln	missense_variant	Exon 42 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5642G>A	p.Arg1881Gln	missense_variant	Exon 44 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5408G>A	p.Arg1803Gln	missense_variant	Exon 42 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5375G>A	p.Arg1792Gln	missense_variant	Exon 41 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5573G>A	p.Arg1858Gln	missense_variant	Exon 43 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5552G>A	p.Arg1851Gln	missense_variant	Exon 44 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5531G>A	p.Arg1844Gln	missense_variant	Exon 42 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5408G>A	p.Arg1803Gln	missense_variant	Exon 42 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5408G>A	p.Arg1803Gln	missense_variant	Exon 42 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5498G>A	p.Arg1833Gln	missense_variant	Exon 42 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5498G>A	p.Arg1833Gln	missense_variant	Exon 42 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5498G>A	p.Arg1833Gln	missense_variant	Exon 42 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5498G>A	p.Arg1833Gln	missense_variant	Exon 42 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5492G>A	p.Arg1831Gln	missense_variant	Exon 43 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5483G>A	p.Arg1828Gln	missense_variant	Exon 43 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5468G>A	p.Arg1823Gln	missense_variant	Exon 43 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5465G>A	p.Arg1822Gln	missense_variant	Exon 42 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5465G>A	p.Arg1822Gln	missense_variant	Exon 42 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5465G>A	p.Arg1822Gln	missense_variant	Exon 42 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5459G>A	p.Arg1820Gln	missense_variant	Exon 42 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5450G>A	p.Arg1817Gln	missense_variant	Exon 42 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5432G>A	p.Arg1811Gln	missense_variant	Exon 41 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5432G>A	p.Arg1811Gln	missense_variant	Exon 41 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5426G>A	p.Arg1809Gln	missense_variant	Exon 41 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5408G>A	p.Arg1803Gln	missense_variant	Exon 42 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5408G>A	p.Arg1803Gln	missense_variant	Exon 42 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5408G>A	p.Arg1803Gln	missense_variant	Exon 42 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5408G>A	p.Arg1803Gln	missense_variant	Exon 42 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5408G>A	p.Arg1803Gln	missense_variant	Exon 42 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5399G>A	p.Arg1800Gln	missense_variant	Exon 42 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5375G>A	p.Arg1792Gln	missense_variant	Exon 41 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000145 AC: 3 AN: 206278 Hom.: 0 AF XY: 0.00000893 AC XY: 1 AN XY: 111986

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000677

Gnomad SAS exome AF: 0.0000376

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000112

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000188 AC: 27 AN: 1435548 Hom.: 0 Cov.: 34 AF XY: 0.0000183 AC XY: 13 AN XY: 711304

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000105

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000191

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74352

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Sep 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1803Q variant (also known as c.5408G>A), located in coding exon 42 of the CACNA1C gene, results from a G to A substitution at nucleotide position 5408. The arginine at codon 1803 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Long QT syndrome Benign:1

Aug 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0093	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.087
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.0093	T
MutationAssessor	Benign	1.6	.;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.87	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.30
Sift	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;T;T;T;T;T;.
Sift4G	Benign	0.61	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.66, 0.49, 0.26, 0.12, 0.84, 0.60, 0.046, 0.030, 0.75, 0.77, 0.46, 0.0	.;P;P;B;B;P;P;P;B;B;P;P;P;P;P;.;P;P;.;.;.;B;.
Vest4		0.21
MutPred		0.42		.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at L1846 (P = 8e-04);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.65
MPC		0.22
ClinPred		0.12	T
GERP RS		3.0
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201918158; hg19: chr12-2788926;